Reference - Detail
|Author||Thornton G, Wilkinson CR, Toone WM, Jones N.|
|Title||A novel pathway determining multidrug sensitivity in Schizosaccharomyces pombe.|
In this study, we show that a mutation isolated during a screen for determinants of chemosensitivity in S. pombe results in loss of function of a previously uncharacterized protein kinase now named Hal4. Hal4 shares sequence homology to Hal4 and Hal5 in S. cerevisiae, and previous evidence indicates that these kinases positively regulate the major potassium transporter Trk1,2 and thereby maintain the plasma membrane potential. Disruption of this ion homeostasis pathway results in a hyperpolarized membrane and a concomitant increased sensitivity to cations. We demonstrate that a mutation in hal4+ results in hyperpolarization of the plasma membrane. In addition to the original selection agent, the hal4-1 mutant is sensitive to a variety of chemotherapeutic agents and stress-inducing compounds. Furthermore, this wider chemosensitive phenotype is also displayed by corresponding mutants in S. cerevisiae, and in a trk1deltatrk2delta double deletion mutant in S. pombe. We propose that this pathway and its role in regulating the plasma membrane potential may act as a pleiotropic determinant of sensitivity to chemotherapeutic agents.
|MeSH||Cation Transport Proteins / genetics Cation Transport Proteins / metabolism Cation Transport Proteins / pharmacology Cations / metabolism Cations / pharmacology Cell Membrane / metabolism Dose-Response Relationship, Drug Drug Resistance, Multiple, Fungal / genetics* Escherichia coli / genetics Gene Expression Regulation, Fungal Genes, Fungal Membrane Potentials Mutation / physiology Potassium Chloride / metabolism Potassium Chloride / pharmacology Protein Kinases / genetics* Protein Kinases / metabolism Protein Kinases / pharmacology Protein-Serine-Threonine Kinases Saccharomyces cerevisiae Proteins / genetics Saccharomyces cerevisiae Proteins / metabolism Saccharomyces cerevisiae Proteins / pharmacology Schizosaccharomyces / drug effects* Schizosaccharomyces / genetics Schizosaccharomyces / metabolism Schizosaccharomyces pombe Proteins / metabolism Schizosaccharomyces pombe Proteins / pharmacology Sequence Homology|
|WOS Category||GENETICS & HEREDITY CELL BIOLOGY|